The present invention relates to a crystalline form of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine and to methods for the production of that crystalline form.
N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine of formula (1) is a known substance having therapeutic utility in depressing blood glucose levels. ##STR1##
N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine is disclosed in Japanese Patent Application Laid Open No. 63-54321 (equivalent to EP-A-196222 and US 4,816,484) and in J. Med. Chem. 32, 1436. The Japanese application describes how the compound may be crystallized from aqueous methanol to yield crystals having a melting point of 129.degree. to 130.degree. C. These crystals are in a crystalline form referred to herein as "B-type". The X-ray powder diffraction pattern and infra-red spectrum of B type crystals are shown in FIGS. 1 and 2 respectively.
The known B-type crystals suffer from problems of instability, especially when subjected to mechanical grinding. The instability results, for example, in conversion of the B-type crystals into other forms. The instability of the B-type crystals means that they are not ideal for use in medicine. It is in general desirable that a medicinal product containing a crystalline active ingredient have a composition which is well defined and stable in terms of the crystalline form of the active ingredient. Conversion of one crystalline form into unknown amounts of different, or amorphous, forms during processing or storage is undesirable and in many cases would be regarded as analogous to the appearance of unquantified amounts of impurities in the product.
The present inventors have discovered a method for producing a crystalline form of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine having improved stability over the known B-type. For instance, the crystals according to one aspect of the present invention have enhanced stability to grinding. Such crystals are therefore more suitable for use in medicines than those of the B-type. The crystals having enhanced stability have been designated "H-type" by the inventors.